Compositions and methods useful for the treatment of neuromyelitis optica spectrum disorders

ABSTRACT

Compositions and methods useful for the treatment of neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD) are disclosed.

FIELD OF THE INVENTION

The invention relates to the fields of central nervous system andneuromyelitis optica (NMO) spectrum disorders. More specifically, theinvention provides an anti-inflammatory formulation and methods of usethereof which ameliorate or reduce the symptoms of NMO.

BACKGROUND OF THE INVENTION

Numerous publications and patent documents, including both publishedapplications and issued patents, are cited throughout the specificationin order to describe the state of the art to which this inventionpertains. Each of these citations is incorporated herein by reference asthough set forth in full.

Neuromyelitis optica spectrum disorders (NMOSD) include limited forms ofDevic's disease, such as single or recurrent events of longitudinallyextensive transverse myelitis, bilateral simultaneous or recurrent opticneuritis, asian optic-spinal multiple sclerosis, optic neuritisassociated with systemic autoimmune disease, optic neuritis ortransverse myelitis associated with lesions in specific brain areas suchas the hypothalamus, periventricular nucleus, and brainstem, and NMO-IgGnegative NMO: AQP4 antibody-seronegative NMO.

Neuromyelitis optica (NMO or Devic's disease) is an inflammatory,demyelinating syndrome of the central nervous system that ischaracterized by severe attacks of optic neuritis and transversemyelitis, which, unlike the attacks in multiple sclerosis, commonlyspare the brain in the early stages.

In developed nations, neuromyelitis optica disproportionately strikesnon-white populations, in which multiple sclerosis is rare.Neuromyelitis optica presents with clinical, neuroimaging, andlaboratory findings that distinguish it from multiple sclerosis.Moreover, the detection of neuromyelitis optica immunoglobulin G(NMO-IgG), an autoantibody, in the serum of patients with neuromyelitisoptica, distinguishes neuromyelitis optica from other demyelinatingdisorders. NMO-IgG binds to aquaporin 4 which is the main channel thatregulates water homoeostasis in the central nervous system. NMO-IgG isalso detected in the serum of patients with disorders related toneuromyelitis optica, including Asian optic-spinal multiple sclerosis,recurrent transverse myelitis associated with longitudinally extensivespinal cord lesions, recurrent isolated optic neuritis, and opticneuritis or transverse myelitis in the context of certain organ-specificand non-organ-specific autoimmune diseases.

NMO patients are currently treated using agents which reduce symptomsand reduce or prevent relapses. No cure for NMO or NMOSDs is currentlyavailable. Most individuals with NMO have an upredictable, relapsingcourse of disease with attacks occurring months or years apart.Disability is cumulative, the result of each attach damaging new areasof myelin. Clearly, a need exists for improved treatments for thisdevastating disease which can limit the neurologic dysfunction thatresults from successive acute relapses of NMO.

SUMMARY OF THE INVENTION

In accordance with the present invention, a method of treating ordelaying the progression of a CNS disorder alleviated by inhibitingcomplement immune system activation in a patient in need of suchtreatment is disclosed. An exemplary method comprises administering,during an active CNS attack, a therapeutically effective amount ofC1-esterase inhibitor (C1-INH) alone or in combination with other agentsuseful for treatment of such CNS disorders. In a preferred embodiment,the disorder is neuromyelitis optica (NMO) or neuromyelitis opticaspectrum disorder (NMOSD). Such treatment can be during the acute phaseof onset or soon thereafter and is preferably of short duration.

In one aspect, the C1-esterase inhibitor (C1-INH) comprises a humanplasma-derived C1-INH (hC1-INH) or a recombinant C1-INH (rC1-INH) andthe disorder is selected from the group consisting of neuromyelitisoptica (NMO) or Devic's disease, single or recurrent events oflongitudinally extensive transverse myelitis, bilateral simultaneous orrecurrent optic neuritis, asian optic-spinal multiple sclerosis, opticneuritis associated with systemic autoimmune disease, optic neuritis ormyelitis associated with lesions in specific brain areas such as thehypothalamus, periventricular nucleus, and brainstem, and NMO-IgGnegative NMO: AQP4 antibody-seronegative NMO. In a particularlypreferred embodiment, the disorder is NMO and said C1 esterase inhibitoris CINRYZE®.

In another aspect of the invention, the C1-INH is administered incombination with another agent useful for treating NMO or NMOSD. Suchagents/treatments include without limitation, plasmapheresis and/oradministration of intravenous immunoglobulin preparations,administration of mycopohenolate, rituximab and/or eculizubab. Incertain approaches, the agents/treatments are administered concurrently.In other approaches, they are administered sequentially.

Also within the scope of the present invention is a pharmaceuticalcomposition for treating or delaying the progression of a disordercaused by alleviated by inhibiting alternative pathway complement immunesystem activation in a patient in need of such treatment, thecomposition comprising administration of an activation inhibiting amountof a C1-esterase inhibitor (C1-INH); and optionally, a biologicallyactive agent selected from the group consisting of, intravenous immunetherapy, mycopohenolate, rituximab and/or eculizubab or a combinationthereof; and a pharmaceutically acceptable carrier medium.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a photograph (Roemer et al. (2007) Brain 130:1194-1205)showing the classic complement deposition in NMO lesions in both the rimpattern (left) and rosette pattern. Staining is for C9neo.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the discovery that C1-esteraseinhibitor (C1-INH) protein may be advantageously administered to NMO andNMOSD patients who present with relapsing autoimmune disease targetingthe spinal cord and optic nerve leading to paralysis and blindness. Ithas been unexpectedly discovered that early short term treatment withC1-INH, as an adjunct to intravenous corticosteroid immunosuppressivetherapy (such as IV methylprednisolone) and plasmapheresis in thosepatients who do not respond to IV steroids (“standard-of-care”), canreduce the damage to the patients nervous system compared to“standard-of-care” alone. As a further advantage to this approach, thepresent inventors have discovered that early and/or short term durationtreatment with C1-INH can produce a durable (longer term) reduction indisease burden post cessation of treatment.

In a preferred embodiment of the invention, the C1-INH is CINRYZE®. Apreferred aspect of the invention is where the patients are treated withconventional intravenous immune therapy (e.g., a syntheticglucocorticoid, such as methylprednisolone). In an alternativeembodiment, the IV immunotherapy includes other known therapies fortreating NMO, for example, plasmapheresis and/or intravenousimmunoglobulin preparations. Other approaches include off label uses ofanti-lymphocyte preparations, rituximab (antibody against CD20),mycophenolate and/or eculizumab (monoclonal antibody against terminalcomplement cascade protein C5).

C1 esterase inhibitor (C1-INH) is an endogenous plasma protein (or afunctional analog thereof) in the family of serine protease inhibitors(SERPINs) and has broad inhibitor activity in the complement, contact,and coagulation pathways. C1-INH inhibits the classical pathway of thecomplement system by binding C1r and C1s and inhibits themannose-binding lectin-associated serine proteases in the lectinpathway. A nanofiltered plasma derived C1-INH (Cinryze®; Viropharma) isFDA approved for routine prophylaxis against angioedema attacks inadolescent and adult patients with hereditary angioedema (HAE), adisease characterized by constitutional deficiency or dysfunction ofendogenous C1 esterase inhibitor.

Cinryze® is known to be well tolerated in humans via the experience inpatients with HAE studied in randomized trials as well as in anextension trial. The most frequent adverse events reported at the dosesused for HAE were headaches and nasopharyngitis. In more than four yearsof post-marketing surveillance, there have been no safety concerns forinfectious events that could be attributed to Cinryze®. Moreover, plasmaderived formulations of C1-INH have been evaluated for their clinicaluse in pilot studies of sepsis, ischemia-reperfusion injury, andcapillary leak in bone marrow transplantation. Thus, C1-INH is an idealtherapeutic, either alone or as part of a combination therapy, fordiseases that implicate, for example, the classical complement pathway(e.g., antibody-mediated diseases) and of the lectin pathway (e.g.,ischemia reperfusion injury).

With respect to the present invention, the C1-INH may be, for example,an isolated human plasma derived C1-INH (hC1-INH) or a recombinantC1-INH (rC1-INH). In a preferred aspect, the C1-INH is rC1-INH.

The following definitions are provided to facilitate an understanding ofthe present invention.

“Neuromyelitis optica spectrum disorders (NMOSD), include, for example,neuromyelitis optica (NMO) or Devic's disease, limited forms of Devic'sdisease, such as single or recurrent events of longitudinally extensivetransverse myelitis, and bilateral simultaneous or recurrent opticneuritis, asian optic-spinal multiple sclerosis, optic neuritisassociated with systemic autoimmune disease, optic neuritis or myelitisassociated with lesions in specific brain areas such as thehypothalamus, periventricular nucleus, and brainstem, NMO-IgG negativeNMO: AQP4 antibody-seronegative NMO.

As used herein, “administering” refers to a method of delivering acomposition of the invention (e.g., Cinryze®) alone and in combinationwith agents known to be useful for ameliorating NMO and NMOSD symptomsto the patient. Such methods are well known to those skilled in the artand include, but are not limited to, oral, nasal, intravenous,intramuscular, intraperitoneal, subcutaneous, intrathecal, intradermal,or topical administration. The route of administration can depend on avariety of factors, such as the therapeutic goals. Compositions of theinvention may be administered on a continuous or an intermittent basis.Methods for formulating and subsequently administering therapeuticcompositions are well known to those skilled in the art. See, forexample, Remington, 2000, The Science and Practice of Pharmacy, 20thEd., Gennaro & Gennaro, eds., Lippincott, Williams & Wilkins. The doseadministered will depend on many factors, including the mode ofadministration and the formulation. Typically, the amount in a singledose is an amount that effectively reduces the level of NMO antigenicpolypeptides or NMO-specific autoantibodies in an individual withoutexacerbating the disease symptoms. A preferred feature of the inventionentails self administration of C1-INH via systemic (IV) or subcutaneousinjection in appropriate dosage forms.

The term “effective amount,” as used herein, refers to the quantity of acompound or composition that achieves a beneficial clinical outcome whenthe compound or composition is administered to a patient. For example,when a composition of the invention is administered to a patient with,intravenous immune therapy (and possibly along with plasmapheresis), a“beneficial clinical outcome” includes the reduction in the neurologicdeficits caused by optic neuritis (visual loss/blindness), transversemyelitis (paralysis, sensory loss, loss of bowel/bladder function,potential brainstem dysfunction), and/or other medical sequelae that mayresult as a consequence of neurologic dysfunction from acute relapses ofNMO/NMOSD which could negatively impact the longevity of the patient.

The term “early” as used herein regarding treatment, refers to thetiming of treatment which may advantageously occur or be initiatedimmediately upon attack onset, or within 7 days from the onset of theCNS attack, more preferably within 5 days. A preferred timing is within72 hours, more preferably within 24 hours, and most preferably within 8hours of onset of an acute CNS attack. An alternate feature of theinvention is where “early” denotes the initiation of treatment of apatient within 24 hours of pro-drome of an acute CNS attack in saidpatient, more preferably within 8 hours, and more preferably within 4hours.

As used herein, “short term duration” with regard to treatment, refersto drug treatments which occur between 1 to 10 days, more preferablybetween 3 to 7 days and most preferably for 5 days.

As used herein, EDSS refers to “The Kurtzke Disability Status Scale(DSS)” which was developed by Dr. John Kurtzke in the 1950s to measurethe disability status of people with multiple sclerosis. This scale wasmodified several times to more accurately reflect the levels ofdisabilities clinically observed. The scale was renamed the KurtzkeExpanded Disability Status Scale (EDSS). The EDSS provides a total scoreon a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 referto people with a high degree of ambulatory ability and the subsequentlevels 5.0 to 9.5 refer to the loss of ambulatory ability. The range ofmain categories include (0)=normal neurologic exam; to (5)=ambulatorywithout aid or rest for 200 meters; disability severe enough to impairfull daily activities; to (10)=death due to MS. In addition, it alsoprovides eight subscale measurements called Functional System (FS)scores. This scale is also is also appropriate for scoring NMO and NMOSDpatients.

The term “isolated,” as used herein in describing a material, forexample, refers to material removed from its original environment (e.g.,the natural environment if it is naturally occurring). For example, anaturally-occurring polypeptide (i.e., protein) present in a livinganimal is not isolated, but the same polypeptide, separated from some orall of the coexisting materials in the natural system, is isolated.

Moreover, the “polypeptides” or “proteins” used in practicing thepresent invention may be natural proteins, synthesized proteins, or maybe preferably recombinant proteins. Further, the proteins describedherein can be naturally purified products, or chemically synthesizedproducts, or recombinant products from prokaryotic or eukaryotic hosts(e.g., bacteria, yeast, higher plant, insect, or mammalian cell). Suchproteins can be glycosylated or non-glycosylated according to thedifferent hosts used.

Turning to the recombinant proteins used in practicing the invention,the recombinant C1-INH (rC1-INH) proteins can be expressed or producedby conventional recombinant DNA technology, using a polynucleotidesequence specific to C1-INH as known in the art. Generally, suchrecombinant procedure comprises the following steps:

-   (1) transfecting or transforming the appropriate host cells with the    polynucleotide or its variants encoding C1-INH protein of the    invention or the vector containing the polynucleotide;-   (2) culturing the host cells in an appropriate medium; and-   (3) isolating or purifying the protein from the medium or cells.

Regarding the invention more generally, in methods of treating NMOdiseases, C1-INH may be used in combination with an additionalbiologically active agent effective for treating acute relapse of NMO inorder to limit the disability from individual attacks and, over time,reduce overall morbidity and disease burden that accrues from multipleattacks of NMO. Moreover, such biologically active agents may notprovide complete treatments for NMO disorders and may in fact providemerely a partial or incomplete treatment, such as in the case ofeculizumab. Therefore, in certain preferred aspects of the method of theinvention, a C1-INH may be administered to a patient in combination withone or more of the agents listed above (e.g., co-administration).

When applying the method of the invention by co-administration, whereseparate dosage formulations are used, the C1-INH and biologicallyactive agent can be administered concurrently, or separately atstaggered times, i.e., sequentially. In practice, the agents of theinvention may be administered as separate dosage units or formulated foradministration together, according to procedures well known to thoseskilled in the art. See, for example, Remington: The Science andPractice of Pharmacy, 20th ed., A. Genaro et al., Lippencot, Williams &Wilkins, Baltimore, Md. (2000). Preferably, the C1-INH is administeredconcurrently with the biologically active agent. In other preferredco-administration strategies, the C1-INH may be administered, forexample, before administration of the biologically active agent, afteradministration of the biologically active agent, or concomitantly withthe administration of the biologically active agent. Additionally, theC1-INH may be administered concurrently with the biologically activeagent where the amount or concentration of the biologically active agentis decreased or tapered with respect to the C1-INH, wherein the amountor concentration of the C1-INH is increased, decreased, or fixed.

Suitable methods of introduction of compositions of the invention to apatient include but are not limited to intradermal, intramuscular,intraperitoneal, intravenous, subcutaneous, intranasal, intraocular,epidural, and oral routes. Moreover, compositions of the invention maybe administered by infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral mucosa, rectal, andintestinal mucosa, etc.). Administration may further be systemic orlocal. And administration can be daily, weekly, monthly, etc.

The orally administered dosage unit may be in the form of tablets,caplets, dragees, pills, semisolids, soft or hard gelatin capsules,aqueous or oily solutions, emulsions, suspensions or syrups.Representative examples of dosage forms for parenteral administrationinclude injectable solutions or suspensions, suppositories, powderformulations, such as microcrystals or aerosol spray. The compositionmay also be incorporated into a conventional transdermal deliverysystem.

Additionally, in certain situations, compounds used in practicing theinvention may be delivered as pharmaceutical compositions that include apharmaceutically acceptable carrier medium. For example, the inventionincludes a pharmaceutical composition for treating or delaying theprogression of a NMO disorder alleviated by inhibition of C1 esteraseactivity, in a patient in need of such treatment, the compositioncomprising a C1-esterase inhibitor (C1-INH); an additional biologicallyactive agent, such as intravenous immune therapy, mycopohenolate,rituximab and/or eculizubab, or a combination thereof; and apharmaceutically acceptable carrier medium.

As used herein, the expression “pharmaceutically acceptable carriermedium” includes any and all solvents, diluents, or other liquidvehicle, dispersion or suspension aids, surface agent agents, isotonicagents, thickening or emulsifying agents, preservatives, solid binders,lubricants, fillers and the like as suited for the particular dosageform desired. Remington: The Science and Practice of Pharmacy, 20thedition, A. R. Genaro et al., Part 5, Pharmaceutical Manufacturing, pp.669-1015 (Lippincott Williams & Wilkins, Baltimore, Md./Philadelphia,Pa.) (2000)) discloses various carriers used in formulatingpharmaceutical compositions and known techniques for the preparationthereof. Except insofar as any conventional pharmaceutical carriermedium is incompatible with the compositions described herein, such asby producing an undesirable biological effect or otherwise interactingin an deleterious manner with any other component(s) of a formulationcomprising the active agent(s), its use is contemplated to be within thescope of this invention.

More specifically, in the production of solid dosage forms, thepharmaceutical composition may be mixed with pharmaceutically inert,inorganic or organic excipients, such as lactose, sucrose, glucose,gelatine, malt, silica gel, starch or derivatives thereof, talc, stearicacid or its salts, dried skim milk, vegetable, petroleum, animal orsynthetic oils, wax, fat, polyols, and the like. Liquid solutions,emulsions or suspensions or syrups one may use excipients such as water,alcohols, aqueous saline, aqueous dextrose, polyols, glycerine, lipids,phospholipids, cyclodextrins, vegetable, petroleum, animal or syntheticoils. Suppositories may include excipients, such as vegetable,petroleum, animal or synthetic oils, wax, fat and polyols. Aerosolformulations may include compressed gases suitable for this purpose,such as oxygen, nitrogen and carbon dioxide. The pharmaceuticalcomposition or formulation may also contain one or more additivesincluding, without limitation, preservatives, stabilizers, e.g., UVstabilizers, emulsifiers, sweeteners, salts to adjust the osmoticpressure, buffers, coating materials and antioxidants.

The present invention further provides controlled-release,sustained-release, or extended-release therapeutic dosage forms for thepharmaceutical composition, in which the composition is incorporatedinto a delivery system. This dosage form controls release of the activeagent(s) in such a manner that an effective concentration of the activeagent(s) in the bloodstream can be maintained over an extended period oftime, with the concentration in the blood remaining relatively constant,to improve therapeutic results and/or minimize side effects.Additionally, a controlled-release system would provide minimum peak totrough fluctuations in blood plasma levels of the active agent.

Additionally, various delivery systems are known and can be used toadminister compositions that comprise C1-INH, or C1-INH in combinationwith a biologically active agent, such as eculizumab. For example, suchcompositions may be encapsulated in liposomes, microparticles, andmicrocapsules, for example.

The methods of the present invention will normally include medicalfollow-up to determine the therapeutic or prophylactic effect broughtabout in the patient undergoing treatment with the compound(s) and/orcomposition(s) described herein.

Turning to the use of C1-INH as a treatment for disease morespecifically, C1-INH may be used for treatment of NMO and relatedneuromyelitis optica spectrum disorders (NMOSD) in vivo. The results ofthe experiments described in the following example demonstrate thatcommercially available plasma-derived C1-INH can limit the neurologicdisability from individual attacks and, over time, reduce the overallmorbidity and disease burden that accrues from multiple attacks of NMO.

The following example is provided to describe the invention in furtherdetail. This example is provided for illustrative purposes only and isnot intended to limit the invention in any way.

Example I CINRYZE® (C1 Esterase Inhibitor [Human]) for the Treatment ofAcute Optic Neuritis and/or Transverse Myelitis in Neuromyelitis Opticaand Neuromyelitis Optica Spectrum Disorder

NMO is a severe, demyelinating autoimmune disease of the central nervoussystem that preferentially affects the optic nerves and spinal cord.Although historically considered a subtype of multiple sclerosis (MS)with overlapping symptoms, NMO is distinct radiologically andprognostically and has a pathophysiology unresponsive to typical MStreatments (Weinshenker et al., (2007) Arch Neurol 64:899-901);Kimbrough, et al., (2012). In 2004, an antibody targeting the waterchannel protein, aquaporin-4, was found to be associated with NMO.Compared to MS, NMO exhibits an older age at onset, a poorer prognosis,and a rarity of cerebrospinal fluid oligoclonal IgG bands. NMO attackstypically produce moderate to severe disability that leads toaccumulation of disability with each attack; between attacks, patientsgenerally remain neurologically stable without evidence of progressivedeterioration. Therefore, it is crucial that aggressive treatment foreach relapse is optimized to prevent disability.

NMO affects predominantly females, with a female to male ratio of 6.5:1.The relative frequency of NMO among demyelinating disorders is quitevariable, being higher in Asian, Hispanic and African populations andlower among Caucasians. The few population-based prevalence studies ofNMO conducted provide prevalence rates of 0.32 to 3.1 per 100,000 in thenon-white population (Nandhagopal, et al., (2010) Postgrad Med J86:153-159).

Clinically definite NMO is defined by a history of optic neuritis andhistory of transverse myelitis with a non-MS brain MRI, longitudinallyextensive myelitis lesions and/or presence of the NMO-IgG biomarker.Seronegative NMO patients with transverse myelitis and optic neuritismust have longitudinally extensive myelitis and a brain MRI that is nottypical for multiple sclerosis. Seronegative NMO is a group that has notbeen adequately characterized for widespread inclusion in clinicaltrials. A third group, NMOSD, is identified as AQP4 antibody positiveindividuals with either optic neuritis or transverse myelitis.

NMOSD comprise the spatially limited syndromes of longitudinallyextensive transverse myelitis (LETM), recurrent isolated optic neuritis(RION)/bilateral optic neuritis (BON), and Asian opticospinal multiplesclerosis (OSMS), as long as patients test positive for the anti-AQP4antibody (Sellner, et al., (2010) European J. Neurol 17:1019-1032).Bizzoco, et al., reported that 7 of 13 (56%) NMOSD patients from Tuscanydeveloped clinically definite NMO after a follow-up time of at least 2years with the other six (46%) remaining NMOSD (Bizzoco et al., (2009)J. Neurol 256:1891-1898). Weinshenker et al., (supra) prospectivelystudied 29 patients with a first event of LETM. Within 1 year, 6 of the11 seropositive (AQP4+) patients had a relapse of myelitis (indicativeof recurrent transverse myelitis) or developed optic neuritis(indicative of neuromyelitis optica). By contrast, no seronegativepatients relapsed over 1-7 years follow-up. NMO and Asian OSMS havesimilar neuroimaging, serological, and immunopathologicalcharacteristics, and the difference is primarily one of classificationas in Japan these individuals are diagnosed with MS, but in NorthAmerica and Europe, these patients are diagnosed with NMO (Matsuoka, etal., (2007) Brain 130:1206-23; Wingerchuk et al., (2007) Lancet Neurol6:805-815).

The current standard of care for treatment of acute NMO attacks of bothoptic neuritis and transverse myelitis is a 5-day course of high dosemethylprednisolone (1000 mg daily)(Kimbrough, supra 2012). In somepatients, this course of steroid treatment is sufficient to suppress CNSinflammation and reverse some neurologic dysfunction. Factors that maypredict success with steroids alone include a small CNS lesion caughtearly in the process and concurrent preventive immunosuppression. Inmany patients, steroids are not sufficient to suppress CNS inflammation,and treatment escalation to plasma exchange is necessary. Five cycles of1.0-1.5 volume exchanges require an additional 2-week inpatienthospitalization and a central line catheter. Plasma exchange carries a4-10% risk of line infection or thrombotic complications. Despite theserisks, plasma exchange is standard of care in steroid-unresponsivepatients because it is 50-70% effective in reducing active CNSinflammation and reducing inflammatory damage in this patient population(Szczepiorkowski et al., (2010) J Clin Apher 25(3):83-177). Ultimately,neurologic recovery after high dose steroids and plasma exchange can bestratified into three groups: a group that does not improve at all, agroup that improves some but maintains a significant neurologic deficitand a group that improves well if not back to baseline.

The rationale for using C1-esterase inhibitor (CINRYZE®) in NMO is basedon pathology showing a prominent role for complement in active NMOlesions (Luchinetti et al. (2002) Brain 125:1450-1461; Misu et al.(2007) Brain 130:1224-1234; Roemer et al. (supra, 2007). NMO is notunique in involving complement, which may have a pathogenic role inother demyelinating diseases including multiple sclerosis (Prineas,2012). However, NMO is characterized by its complement involvementdepositing in a rim or rosette pattern in all active lesions (FIG. 1).In vitro, complement is critical in mediating damage initiated byanti-AQP4 antibody binding to astrocytes (Hinson et al., (2007)Neurology 69:2221-2231; Kinoshita et al., (2008) NeuroReport20(5):508-512). The effector of antibody triggered cell damage is thecomplement cascade (Marignier et al. (2010) Brain 133:2578-2591; Sabateret al. (2009) J. of Neuroimmunology 215:31-35) and blocking thecomplement cascade with C1-inhibitor prevents damage ex vivo (Saadoun etal. (2012) Annals of Neurology 71(3):323-333). Based on this mountingevidence the consensus in the field is that prevention of the complementcascade in the CNS would ameliorate the damage caused in NMOinflammatory attacks. This was the basis of the first open labelprospective trial in NMO using eculizumab (Soliris®). Results from thistrial are now publically available. In contrast to the eculizumab trial,which is a prevention trial, the inventive approach described hereinprovides for complement inhibition as acute treatment during an activeCNS attack. This approach is designed to administer the inhibitory drugwhen complement damage is at its peak. This approach minimizes theexposure to this medication and dramatically reduces cost of carecompared to eculizumab therapy.

Patients with NMO do not lack natural C1-esterase inhibitor, butadministering pd C1-INH to increase endogenous levels appears tosuppress the complement pathways. Notably, in patients with hyperactivecomplement activation, this approach has been shown to be beneficial insepsis and myocardial infarction. In sepsis, complement activation is acontributing factor to end organ failure. Notwithstanding concerns thatcomplement inhibition would prevent bacterial clearance, high doseC1-esterase inhibitor provided to sepsis patients reduced sepsis-inducedmortality and all-cause mortality (Ignonin et al., (2012) Crit Care Med40(3):770-777). In myocardial infarction, complement activationparticipates in reperfusion injury and induction of inflammation,leading to reduced coronary perfusion. Several studies have shown abenefit of C1 esterase inhibitors in ameriolorating thecomplement-mediated reperfusion injury (Buerke et al. (1995) Circulation91:393-402; Shandelya et al. (1993) Circulation 88:2812-2826; Weisman etal. (1990) Science 24:146-151; Fattouch et al. (2007) Eur J CardiothoracSurg 32(2):326-332) after myocardial infarction. The rationale behindall of these studies is that in patients with otherwise normalcomplement function, tipping the balance toward complement inhibitioncan reduce end organ damage in certain disease conditions.

Complement-mediated damage is presumed to account for a significantcomponent of the pathological changes observed in patients with NMO andis supported by ex vivo studies of the role of complement in NMO.Similar to the studies in sepsis and myocardial infarction, therationale for adding human C1-esterase inhibitor to the treatment forNMO acute exacerbations is to tip the balance toward complementsuppression in an effort to reduce complement-mediated neurologicdamage.

We conducted an open-label phase 1b safety and proof-of-concept trial in10 subjects with NMO-IgG seropositive NMO or NMO spectrum disease(NMOSD) who presented with acute transverse myelitis and/or opticneuritis. In addition to treating with 1 gram of daily intravenousmethylprednisolone, we infused 2000 Units of C1-esterase inhibitor daily×3 days beginning on day 1 of hospitalization. The primary outcomemeasure was safety, and the secondary efficacy measure was change inExpanded Disability Scale Scores (EDSS).

Results

Ten NMO-IgG seropositive subjects were enrolled, 7 of whom presentedwith acute transverse myelitis and 3 with acute optic neuritis.C1-esterase inhibitor (Cinryze®) proved safe in all 10 NMO subjects withno serious adverse events reported. One subject had a headache duringthe first infusion. There were no thromboembolic events or related lababnormalities in any of the subjects. EDSS scores dropped from a medianof 4.5 on admission to 4.0 on discharge and then down to 2.5 on 30-dayfollow up. See Table 1. All but one subject returned to pre-attack EDSSand only one subject required escalation to plasmapheresis.

TABLE I EDSS EDSS score score Study measurement/timing (median) (mean)Baseline (pre-acute NMO 2.75 attack) Admission (NMO acute 4.5 5.45attack) Discharge (post 4.0 4.25 hospitalization) 30-day follow-up 2.53.28Paired non-parametric t testing was used to compare pretreatment EDSSscores to each post treatment EDSS score.

CONCLUSIONS

C1-esterase inhibitor (Cinryze®) is a safe add-on therapy for NMO/NMOSDpatients presenting with acute transverse myelitis and optic neuritis.The evidence provided herein shows a promising benefit with C1-esteraseinhibitor in reducing neurologic disability and improving outcomes.

While certain of the preferred embodiments of the present invention havebeen described and specifically exemplified above, it is not intendedthat the invention be limited to such embodiments. Various modificationsmay be made thereto without departing from the scope and spirit of thepresent invention, as set forth in the following claims.

What is claimed is:
 1. A method of treating or delaying the progressionof neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder(NMOSD) in a patient in need of treatment, the method comprisingadministering to said patient during an active CNS attack one or moredoses of at least 2000 U of C1-esterase inhibitor (C1-INH) per dose, andwherein the one or more doses decreases symptoms of NMO or NMOSD topre-attack levels.
 2. The method according to claim 1, wherein theC1-INH is a human plasma-derived C1-INH or a recombinant C1-INH.
 3. Themethod according to claim 1, wherein the NMOSD is single or recurrentevents of longitudinally extensive transverse myelitis, bilateralsimultaneous or recurrent optic neuritis, Asian optic-spinal multiplesclerosis, optic neuritis associated with systemic autoimmune disease,optic neuritis or myelitis associated with lesions in specific brainareas comprising at least one of the hypothalamus, periventricularnucleus, and brainstem, or NMO-IgG negative NMO:AQP4antibody-seronegative NMO.
 4. The method of claim 1, wherein the one ormore doses of at least 2000 U of C1-INH is administered within 7 daysfrom onset of the active CNS attack.
 5. The method of claim 4, whereinthe one or more doses of at least 2000 U of C1-INH is administeredwithin 72 hours from onset of the active CNS attack.
 6. The method ofclaim 5, wherein the one or more doses of at least 2000 U of C1-INH isadministered within 24 hours from onset of the active CNS attack.
 7. Themethod according to claim 1, further comprising administering to saidpatient an adjunct treatment effective for treating or delaying theprogression of NMO or NMOSD.
 8. The method according to claim 7, whereinthe C1-INH and the adjunct treatment are administered to said patientconcurrently or sequentially.
 9. The method according to claim 7,wherein said adjunct treatment is selected from intravenous immunetherapy, plasmapheresis, administration of mycophenolate, administrationof rituximab, administration of eculizumab, administration ofintravenous immunoglobulin preparations, or a combination thereof. 10.The method according to claim 9, wherein the C1-INH and the adjuncttreatment are administered to said patient concurrently or sequentially.11. The method according to claim 9, wherein the intravenous immunetherapy comprises intravenously administering a glucocorticoid.
 12. Themethod according to claim 11, wherein the C1-INH and the adjuncttreatment are administered to said patient concurrently or sequentially.13. The method according to claim 11, wherein the glucocorticoid ismethylprednisolone.
 14. The method according to claim 12, wherein theC1-INH is a human plasma-derived C1-INH.
 15. The method according toclaim 14, wherein the glucocorticoid is methylprednisolone.
 16. Themethod according to claim 12, wherein the C1-INH is a recombinantC1-INH.
 17. The method according to claim 16, wherein the glucocorticoidis methylprednisolone.